The present invention relates to a novel process for the preparation of xcex1xe2x80x2-N-acyl-xcex1xe2x80x2-chloroketones. The xcex1xe2x80x2-chloroketones produced in accordance with the process of the invention are precursors of hydroxyethylamine isostere sub-units present in many molecules therapeutically useful as inhibitors of angiotensin converting enzyme, renin and HIV-protease.
A process for preparing xcex1-haloketones is described by Kxc3x6nig and Mezger in Chem. Ber., Vol. 98, pages 3733-3747, 1965. The disclosed process involves the reaction of dimethyl-oxo-sulfoniummethylide with isocyanates and ketenes to form xcex2-keto-sulfoniummethylides. On page 3738, in Table 3, there is disclosed treatment of the xcex2-keto-sulfoniummethylides with hydrochloric acid or bromine to form xcex1-chloroketone or xcex1,xcex1-dibromoketone.
Degraw and Cory, Tetrahedron Letters, No. 20, pages 2501xe2x80x942501, 1968, disclose the preparation of xcex1-acetoxy and xcex1-halomethylketones from acyloxosulfonium ylides by the action of acids. This paper also teaches that the selective preparation of xcex1-halo and xcex1-acetoxymethyl ketones by the reaction of halogen acids or organic acids with xcex1-diazoketones is well known. Given that the diazoketones are usually obtained by the reaction of diazomethane with the appropriate acid chloride, the method taught by this paper is not considered attractive for large-scale applications.
Powers and Wilcox, J. Am. Chem. Soc., 92, page 1782, 1970 describe a classical method for the preparation of xcex1-chloroketones involving the conversion of an N-acyl-xcex1-amino acid to a xcex1-diazoketone and subsequent acidolysis with HX. The use of diazomethane in this method makes it impractical for large-scale operations and also imposes safety considerations.
Kowalski et al., J. Org. Chem., Vol. 50, 5140, 1985 and J. Org. Chem., Vol. 57, 7194, 1992, describe homologation of esters to xcex1-bromoketones utilizing the reagent system CH2Br2/LDA/n-BuLi.
Baldwin et al., Synlett, pages 51-53, 1993 describe a process whereby a nucleophilic ring compound, an activated monocyclic xcex2-lactam, is opened by reaction with trimethylsulfoxonium ylide, lithiated sulfones and cuprates to form a variety of functionalized xcex3-keto-xcex1-amino acids that are useful intermediates for the synthesis of natural products.
Chen and Cheng, Tetrahedron Letters, Vol. 38, No. 18, pages 3175-3178, 1997, describes the development of reactions for the preparation of xcex1-chloroketones and proposes a practical process for the preparation of xcex1xe2x80x2-chloroketones of N-carbamate-protected xcex1-amino acids by reaction of lithium diisopropylamide and chloroiodomethane with BOC-L-phenylalanine ethyl ester. This process, however, is disadvantageous in that there is formed the high-boiling, toxic by-product chlorodiiodomethane.
The present invention is directed to an improved process for the preparation of xcex1-N-acyl-xcex1xe2x80x2-chloroketones by the action of a sulfur ylide on aryl esters to generate a keto ylide that is in turn treated with a source of chloride and an organic acid. The present invention is further directed to an improved process for the preparation of corresponding epoxide compounds that are intermediates in the synthesis of an important HIV protease inhibitor.